PROJECT SUMMARY While head and neck squamous cell cancer (HNSCC) is only 5% of all cancers in the United States, the incidence of a subset of HNSCC caused by human papilloma virus (HPV) is increasing rapidly. Conventional treatment of these cancers requires chemotherapy (usually Cisplatin) and radiation. While the HPV positive HNSCC have an improved response to treatment, the overall 5 year survival for HNSCC is only 50% and the short and long term side effects from treatment are significant. Modulation of current effective treatment and new less toxic treatments are needed to improve the long term cures as well as limit the side effects in a progressively younger cancer population that may live with these side effects for 30 to 40 years post treatment. We have previously shown a directed adaptive immune response to HPV positive HNSCC in a mouse model and the importance of the immune response to HPV positive HNSCC has been confirmed in correlative human studies as well. While cisplatin has been described as interfering with DNA, we have found some preliminary evidence for a potential immune stimulating mechanism through a cellular protein, CD154. We have found that the CD154-CD40 interaction, classically described in B and T cell interactions, is required for the clearance of tumors in our model. CD154 is present in human and mouse HNSCC lines and increases after cisplatin treatment. Our hypothesis is cisplatin causes an increase of CD154 in the tumor cell that results in immune mediated clearance of HPV positive HNSCC. This project proposes to define the interaction of the tumors cells and the immune system, determine the mechanism that cisplatin uses to increase CD154, and to improve this cisplatin driven immune clearance through off the shelf immune modulating agents. This project is designed to 1) provide more information about the specific components of the immune system in and around the tumor that are affected by this increase in CD154 through Cisplatin treatment 2) understand the mechanism that Cisplatin uses to increase CD154 in HPV positive tumor cells and 3) Combine immune modulation with Cisplatin treatment in our mouse model of HPV positive HNSCC. This immune modulation will utilize off the shelf antibody and vaccine treatments that are already in clinical application or within a few years of clinical implementation in humans. The data from this project will provide a greater understanding of a common chemotherapy agent, Cisplatin, that may prompt use of the drug in doses and timing that could improve the efficacy of treatment and potentially the long term response of HPV positive cancers. The knowledge gained from this study could be potentially applied to other HPV positive cancers (cervical, anal, etc.) as well as perhaps HPV negative cancers responsive to cisplatin. The long term goal of this project is to understand the modulation of the local tumor environment and to use this information to find treatment regimens that cure patients of cancer with limited side effects.